5-Fluorouracil Response and Optimization STudy (The FROST Trial)

April 21, 2026 updated by: Washington University School of Medicine

The 5-Fluorouracil Response and Optimization STudy (The FROST Trial): A Randomized Phase II Trial of Two Dosage Regimens (2D-Q2W vs 4D-Q3W) of 5-Fluorouracil (5-FU) in Patients With Platinum and PD-1 Inhibitor Pre-treated Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

This randomized phase II trial will characterize the efficacy, adverse event (AE) profile, and safety of two regimens of 5-FU given as 2L+ treatment to patients with RM-HNSCC. Eligible patients for this trial will have previously received platinum and PD-1 inhibitor therapy. The experimental regimen (Arm 1) will comprise the two days every two weeks (2D-Q2W) regimen of 5-FU. The standard regimen (Arm 2) will consist of the four days every three weeks (4D-Q3W) regimen of 5-FU. The primary hypotheses is that each regimen of 5-FU will result in an ORR of 10% of greater assessed by RECIST v1.1 criteria. The study will also describe treatment-related AEs assessed by CTCAE v5.0, dose interruptions, discontinuations, and modifications in each regimen.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
46

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • United States
    • Missouri
      • St Louis, Missouri, United States, 63110
        • Recruiting
        • Washington University School of Medicine
        • Sub-Investigator:
          • Peter Oppelt, MD
        • Sub-Investigator:
          • Esther Lu, PhD
        • Contact:
        • Principal Investigator:
          • Christine Auberle, MD
        • Sub-Investigator:
          • Douglas Adkins, MD
        • Sub-Investigator:
          • Brendan Knapp, MD
        • Sub-Investigator:
          • Jesse Zaretsky, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Histologically or cytologically confirmed:

    • RM-HNSCC of the oral cavity, oropharynx, larynx, or hypopharynx, OR
    • p16+ (HPV-related) level 2-3 neck node and unknown primary site, OR
    • Second primary HNSCC in a previously radiated field not amenable to curative-intent surgery and/or re-radiation.
  • Measurable disease per RECIST 1.1.
  • Previously treated with platinum-based chemotherapy, RM disease within 6 months of definitive cisplatin + radiation therapy (DCisRT) or post-operative adjuvant cisplatin + radiation therapy (POACisRT) OR progressive disease on or after or intolerance to platinum agent given for RM disease.
  • Previously treated with PD-1 inhibitor, RM disease within 6 months of PD-1 inhibitor given as part of curative-intent therapy OR progressive disease on or after PD-1 inhibitor given for RM disease OR intolerance to prior PD-1 inhibitor in the curative or metastatic setting.
  • At least 18 years of age
  • ECOG performance status ≤ 2

  • Adequate bone marrow and organ function as defined below:

    • Absolute neutrophil count ≥ 1.0 K/cumm
    • Platelets ≥ 100 K/cumm
    • Hemoglobin ≥ 8.0 g/dL
    • Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease ≤ 3 x IULN)
    • AST(SGOT)/ALT(SGPT)/Alkaline Phosphatase (ALP) ≤ 3.0 x IULN. For subjects with documented bone metastasis, ALP ≤ 5.0 x IULN.
    • Serum creatinine <3 mg/dL or creatinine clearance > 30 mL/min by Cockcroft- Gault.
  • The effects of 5-FU on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 30 days after last dose of 5-FU
  • Recovery to baseline or ≤ grade 1 from AEs due to prior therapy, unless AEs are clinically nonsignificant and/or stable on supportive therapy (e.g., physiological replacement of corticosteroid). Low-grade or controlled toxicities such as alopecia, ≤ grade 2 hypomagnesemia, or ≤ grade 2 neuropathy are permitted.
  • Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

  • Prior 5-FU given to treat RM-HNSCC.
  • Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial.
  • Currently receiving any other investigational agents.
  • RM or incurable second primary SCC of cutaneous, nasopharynx, paranasal/nasal/sinus origin.
  • DPYD deficiency (poor or intermediate metabolizer) as determined by next generation sequencing through blood or saliva (results of historical testing are accepted).
  • Severe hepatic impairment (Child-Pugh C) or history of hepatitis B or C.
  • Patients with untreated brain metastases. Patients with treated brain metastases are allowed if post-treatment brain-imaging after CNS-directed therapy shows no evidence of progression.
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-FU or other agents used in the study.
  • Pregnant and/or breastfeeding. Women of childbearing potential must have a negative urine pregnancy test within 14 days of study registration.
  • HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Arm 1: 5-Fluorouracil (5-FU) 2D-Q2W
Patients randomized to Arm 1 will receive 5-FU as a 400mg/m2 bolus followed by 2,400 mg/m2 continuous intravenous infusion (CIVI) over a 46 hour time period every 2 weeks on Day 1-2 and Days 15-16. Each cycle is 28 days.
Drug: 5-Fluorouracil
Dose modifications or reductions are determined by patient's tolerability to the drug.
Other Names:
  • 5-FU
  • Adrucil
Active Comparator: Arm 2: 5-Fluorouracil (5-FU) 4D-Q3W
Patients randomized to Arm 2 will receive 5-FU as a 1000g/m2/day continuous intravenous infusion (CIVI) over 4 days every 3 weeks on Day 1-4. Each cycle is 21 days.
Drug: 5-Fluorouracil
Dose modifications or reductions are determined by patient's tolerability to the drug.
Other Names:
  • 5-FU
  • Adrucil

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Overall response rate (ORR)
Time Frame: Start of treatment through completion of treatment (estimated time up to 4 months)
  • ORR, defined as CR and PR per RECIST v1.1.
  • Complete Response (CR): Disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
  • Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Start of treatment through completion of treatment (estimated time up to 4 months)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Incidence of patients requiring a dose reduction due to treatment related adverse events (TRAEs)
Time Frame: Start of treatment through completion of treatment (estimated time up to 4 months)
Start of treatment through completion of treatment (estimated time up to 4 months)
Incidence of patients requiring a dose interruption or delay due to treatment related adverse events (TRAEs)
Time Frame: Start of treatment through completion of treatment (estimated time up to 4 months)
Start of treatment through completion of treatment (estimated time up to 4 months)
Incidence of patients requiring treatment discontinuation due to treatment related adverse events (TRAEs)
Time Frame: Start of treatment through completion of treatment (estimated time up to 4 months)
Start of treatment through completion of treatment (estimated time up to 4 months)
Daily dose intensity
Time Frame: Start of treatment through completion of treatment (estimated time up to 4 months)
Daily dose intensity will be measured as the average daily dose/m2 of 5-FU administered in the treatment interval for each regimen (Days 1-2 and Days 15-16 for Arm 1 and Days 1-4 for Arm 2).
Start of treatment through completion of treatment (estimated time up to 4 months)
Overall Adverse Events (AEs) by grade (3, 4, and 5) and type
Time Frame: Start of treatment to 28 days after completion of treatment (estimated time up to 5 months)
Adverse events are classified and graded by CTCAE v5.0.
Start of treatment to 28 days after completion of treatment (estimated time up to 5 months)
Number of adverse events of specific interest (AESI)
Time Frame: Start of treatment through 28 days after completion of treatment (estimated time up to 5 months)
Adverse events of special interest are as follows: diarrhea, mucositis, palmar-plantar erythrodysesthesia (Hand-Foot Syndrome) (PPE/HRS), neutropenia, and thrombocytopenia. Adverse events are classified by CTCAE v5.0.
Start of treatment through 28 days after completion of treatment (estimated time up to 5 months)
Number of treatment-related deaths
Time Frame: Start of treatment through 28 days after completion of treatment (estimated time up to 5 months)
Start of treatment through 28 days after completion of treatment (estimated time up to 5 months)
Duration of Response (DoR)
Time Frame: From time criteria is met for CR or PR through 3 years after completion of treatment (up to 3 years and 4 months)
  • DoR is defined as the duration from the onset of first response (CR + PR) to disease progression or death for any reason
  • Complete Response (CR): Disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
  • Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
From time criteria is met for CR or PR through 3 years after completion of treatment (up to 3 years and 4 months)
Progression-free survival (PFS)
Time Frame: Start of treatment through 3 years after completion of treatment (up to 3 years and 4 months)
PFS is defined as the time from the date of treatment start to progression or death, which occurs first. The alive patients without progression are censored at the last follow-up.
Start of treatment through 3 years after completion of treatment (up to 3 years and 4 months)
Overall survival (OS)
Time Frame: Start of treatment through 3 years after completion of treatment (up to 3 years and 4 months)
OS is defined as the time from the start of treatment to the date of death, censored at the last follow-up otherwise.
Start of treatment through 3 years after completion of treatment (up to 3 years and 4 months)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Washington University School of Medicine

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
The Joseph Sanchez Foundation

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Christine Auberle, MD, Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 21, 2026

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 31, 2028

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 31, 2031

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 11, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 11, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 19, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 27, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 21, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 202603057

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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